Cell aging, particularly dermal cell aging, has been widely studied. One of the most important factors in cell aging is the formation and accumulation of free radicals inside the cells. As well as natural aging, several environmental factors such as pollutants or ultraviolet radiation are capable of damaging skin cells by increasing the quantity of reactive oxygen species (ROS), altering DNA stability and interfering in cell functions, thus causing cell and tissue aging, and increasing the risk of developing cancer.
When DNA damage is caused two different pathways can be activated depending on the level of alteration caused by this damage, i.e., cells can activate DNA repair pathways or programmed cell death pathways (apoptosis). This ability of the cells to repair the damage limited to DNA or inducing the controlled death of very damaged cells protects the tissues and increases the survival prospects of organisms [Tran H. et al. “DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein”, Science, (2002), 296, 530-534; Kirkwood T B., Austad S N. “Why do we age?”, Nature, (2000), 408, 233-238].
Apoptosis, or programmed cell death, is a common phenomenon in the development of multicellular mechanisms. Cells die as a response to a variety of stimuli and in the case of apoptosis the cell death occurs in a controlled and regulated way. This distinguishes apoptosis from other forms of necrosis where uncontrolled cell death results in cell lysis [Wong R., Journal of Experimental & Clinical Cancer Research, (2011), 30, 1-14]. In the case of apoptosis the cell actively participates in the process inducing its own suicide. According to some conditions, apoptosis depends on transcription and requires over expression of “death genes”, such as p53 tumor suppressor [Khanna K K., Lavin M F., “Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells”, Oncogene, (1993), 8, 3307-3312], proapoptotic genes and some cytokines [Le-Niculescu H. et al. “Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death”, Mol. Cell. Biol., (1999), 19, 751-763]. However, if the level of DNA damage is not very high and the cells functions can be recovered, DNA repair processes will begin [Zhou B B., Elledge S J., “The DNA damage response: putting checkpoints in perspective”, Nature, (2000), 408, 433-439].
One of the possible control strategies of DNA repair and cell apoptosis passes through FOXO (“forkhead transcription factors” subclass O) transcription factors. The family of FOXO transcription factors is a family of proteins which are very well conserved among all the species and it is involved in the maintenance of the integrity of the genome, playing an essential role in longevity and tumor suppression [Calnan D. R. and Brunet A., “The FoxO code”, Oncogene, (2008), 27, 2276-2288]. There are four FOXO transcription factors in mammals, FOXO1, FOXO3, FOXO4 and FOXO6. The FOXO3a transcription factor induces the expression of a series of genes as key functions related to metabolism, tumor suppression, development and longevity. Specifically, FOXO3a induces the expression of genes which allow damaged DNA to be repaired (GADD45, DDB1), genes involved in the regulation of the cell cycle (p21, p27, cyclin G2), in apoptosis (BIM-1, bcl-6, Fas, Trail), in the protection of the cells against oxidative stress (MnSOD, catalase), in gluconeogenesis (PEPCK, Glucose-6-phosphatase), angiogenesis (Sprouty2) or in cell differentiation (Btg1), among others [Ogg S. et al. “The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. Elegans”, Nature, (1997), 389, 994-999; Larsen P L., “Aging and Resistance to Oxidative Damage in Caenorhabditis elegans” Proc Natl Acad Sci USA, (1993), 90, 8905-8909; Tran H. et al. “DNA Repair Pathway Stimulated by the Forkhead Protein Transcription Factor FOXO3a Through the Gadd45 Protein”, Science, (2002), 296, 530-534; Brunet A. et al. “Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor”, Cell, (1999), 96, 857-868; Murphy C. T., “The search for DAF-16/FOXO transcriptional targets: Approaches and discoveries”, Exp Gerontol., (2006), 41(10), 910-21].
One of the consequences of this genetic expression of FOXO3a is for example that FOXO3a is clearly linked to the longevity of human beings; it is described in the literature that activation of FOXO3a induces an increase in the lifespan of the worm C elegans [Dorman J. B. et al. “The age-1 and daf-2 genes function in a common pathway to control the lifespan of C elegans”, (1995), Genetics, 141, 1399-1406], of the fruit fly [Clancy D. J. et al. “Extension of Life-Span by Loss of CHICO a Drosophila Insulin Receptor Substrate Protein”, (2001), Science, 292, 104-106] or mice [Holzenberger M. et al. “IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice”, Nature, (2003), 421(6919), 182-187].
Furthermore, FOXO3a also plays a key role in delaying cell senescence and, therefore, aging [Kim H. K. et al. “Downregulation of Foxo3a Accelerates cellular senescence in HDFs”, J. Geront. A Bio. Sci. Med. Sci., (2005), 60, 4-9].
The relationship of FOXO transcription factors in the development of tumors is also widely described in scientific literature; and it has been demonstrated that an animal model in which the expression of all the FOXO proteins had been suppressed developed a cancerous condition characterized by the presence of abundant thymic lymphomas and hemangiomas [Ji-Hye Paik J. H et al. “FoxOs are lineage-restricted redundant tumor suppressors and critical regulators of endothelial cell homeostasis”, Cell, (2007), 128(2), 309-323]. In the same way, inhibition of the expression of some of the FOXO transcription factors or of their activity can lead to the development of some types of cancer, such as breast cancer [Lin H. et al. “Unregulated miR-96 Induces Cell Proliferation in Human Breast Cancer by Downregulating Transcriptional Factor FOXO3a”, PLoS ONE, (2010), 5(12), e15797].
However, the quantity of FOXO which is active is not constant throughout the lifetime of human beings and with age the quantity of FOXO found in the inactive phosphorylated form increases [Kim H. K. et al. “Downregulation of Foxo3a accelerates cellular senescence in HDFs”, J. Geront. A Bio. Sci. Med. Sci., (2005), 60, 4-9]. It is for this reason that with age the natural abilities of the organism to repair DNA, regulate the cell cycle and protect the cells against oxidative stress are lost, and cell differentiation, aging and the appearance of tumors occurs.
Thus, there is the need to find compounds which stimulate the synthesis of proteins regulated by FOXO and which intervene in the aforementioned processes.